Brain, Vol. 124, No. 6, 1228-1240,
June 2001
© 2001 Oxford University Press
Pattern electroretinograms after cerebral hemispherectomy
Department of Experimental Psychology, University of Oxford, UK
Correspondence to:
Dr Paul Azzopardi, Department of Experimental Psychology, University of Oxford, South Parks Road, Oxford OX1 3UD, UK E-mail: paul.azzopardi{at}psy.ox.ac.uk
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Abstract |
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Cortically blind patients with brain damage restricted to the optic radiations or primary visual cortex may be able to detect and discriminate visual stimuli presented in their field defects, even though they deny seeing them. In contrast, patients who are hemianopic as a result of cerebral hemispherectomy cannot explicitly discriminate visual stimuli in their field defects, even when forced choice procedures are used. A possible explanation for this difference is that retrograde, transneuronal degeneration of the retina, which affects ~85% of wavelength-sensitive ganglion cells (~70% of the total) after damage restricted to striate cortex, could be far more extensive after hemispherectomy, rendering the retina incapable of processing and conveying visual information to the brain. To test this, we assessed retinal ganglion cell function by means of electroretinography in three patients with cerebral hemispherectomy who were functionally blind. Steady-state pattern electroretinograms elicited by achromatic and isoluminant-chromatic (red–green) sinusoidal gratings, whose contrast was temporally modulated, were recorded from both blind and sighted hemiretinae. The electroretinograms were qualitatively indistinguishable from those of a control patient with a unilateral striate cortical lesion with documented visual capacity in his field defect. Within-subject analysis of variance revealed significant differences in the amplitude of the second harmonic (2f0) component of the averaged signal (diagnostic of retinal ganglion cell function) with respect to stimulus, but no significant differences between blind and sighted hemiretinae. This indicates that many retinal ganglion cells must have survived in the hemispherectomized patients. Isoluminant chromatic stimuli tended to elicit stronger signals than achromatic stimuli, which was unexpected given that wavelength-opponent Pß ganglion cells are far more susceptible than broad-band P
ganglion cells to transneuronal degeneration after cortical damage. It suggests that the 2f0 component of the response to isoluminant chromatic stimuli might not reflect the activity of chromatic processes. Overall, the results show that the absence of residual vision in the blind fields of patients with cerebral hemispherectomy cannot be due to complete degeneration of retinal ganglion cells and, by extension, complete degeneration of their subcortical targets. This supports an alternative explanation, which is that intact extrastriate cortex is required for mediating voluntary responses to visual stimuli presented in the scotoma. blindsight; hemispherectomy; parallel processing; retinal degeneration; visual cortex
dLGN = dorsal lateral geniculate nucleus; f0 = fundamental frequency; 2f0 = second harmonic frequency; c.p.d. = cycles per degree; PERG = pattern electroretinogram
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Introduction |
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Brain damage which results in damage or disconnexion of the primary visual cortex (area 17, striate cortex, or V1) causes blindness in the corresponding part of the visual field (Holmes, 1945
). However, some patients with occipital lobe damage have blindsight, which means that they can detect and discriminate visual targets within their field defects when forced-choice procedures are used, despite the fact that they deny seeing anything (Pöppel et al., 1973; Weiskrantz et al., 1974). The range of visual capacities spared in blindsight includes reflexes (e.g. pupillary reflexes), implicit responses (e.g. the effects of unseen stimuli presented in the blind field on reaction times to seen stimuli presented in the good field), and explicit responses (meaning voluntary responses such as pointing and verbal reports when detecting and discriminating stimuli) to static, flickering or moving targets, target location and wavelength (for reviews, see Weiskrantz, 1986; Stoerig and Cowey, 1997).
In principle, residual vision in the scotoma can be explained by the existence of alternative pathways from the retina to centres in the brain other than the striate cortex (Cowey and Stoerig, 1991). The most substantial one is from the retina to the superior colliculus of the midbrain, from where visual information is relayed to the pulvinar nucleus of the thalamus and thence to extrastriate visual cortex such as V2, V3, V4, V5/MT and TE. The contribution of extrastriate pathways to blindsight has been established through experiments with both patients and monkeys with striate cortex lesions. First, neurones in extrastriate cortex can be activated by visual stimuli even in the absence of striate cortex, but only provided the superior colliculus is intact (Rodman et al., 1989, 1990; Gross, 1991; Girard et al., 1991, 1992; Barbur et al., 1993; Bullier et al., 1994). Secondly, blocking the colliculo-pulvinar pathway by lesioning the superior colliculus in monkeys with striate cortex lesions abolishes voluntary responses to visual targets presented in the scotoma (Mohler and Wurtz, 1977).
It is not known whether the superior colliculus alone is sufficient for mediating any of the responses found in blindsight, but patients who have undergone cerebral hemispherectomy, and therefore lack extrastriate as well as striate cortex while retaining pulvinar and superior colliculus, are not only hemianopic, but also unable to respond explicitly to visual targets in their field defects, other than those associated with artefacts such as scattered light and response bias (Campion et al., 1983; King et al., 1996a, b; Barton and Sharpe, 1997; Faubert et al., 1999), or those presented so close to the vertical meridian of the visual field as to impinge on the zone of naso-temporal overlap of retinal ganglion cells (Wessinger et al., 1996). This implies that extrastriate cortex is necessary for mediating voluntary responses in blindsight, or that the destruction of all cortex damages the mid-brain optic centres themselves.
Cortical lesions can cause extensive degeneration of early visual pathways. Lesioning the striate cortex alone causes a rapid retrograde degeneration of projection neurones in the corresponding part of the dorsal lateral geniculate nucleus (dLGN) (Mihailovic et al., 1971) and subsequent transneuronal, retrograde degeneration of ganglion cells in the corresponding part of the retina (van Buren, 1963; Cowey, 1974; Johnson and Cowey, 2000). There are three broad classes of common ganglion cell in the primate retina: P, which have large cell bodies and dendritic fields, broad-band sensitivity, and project to the magnocellular layers of the dLGN; Pß, which have small cell bodies and dendritic fields, spectrally selective responses, and project to the parvocellular layers of the dLGN; and P
, which are morphologically and physiologically heterogeneous and project mainly to the superior colliculus (Perry and Cowey, 1981, 1984, 1985; Perry et al., 1984; Shapley and Perry, 1986). (Their subdivisions need not concern us here.) Of the other classes of rare ganglion cell, the small bistratified cells comprise only 1–2% of ganglion cells in the central 20° of the retina. Nevertheless, they are believed to give rise to the wavelength opponent, koniocellular pathway that innervates the interlaminar cells of the dLGN (for review, see Dacey, 1994). In monkeys, striate cortex lesions affect only the wavelength-sensitive Pß ganglion cells, ~85% of which (corresponding to 70% of the total ganglion cell population) degenerate; P cells, P cells and many small bistratified cells appear to be unaffected (Cowey et al., 1989; Weller and Kaas, 1989; Niida et al., 1990). The ganglion cells that survive probably do so because they retain direct functional contact with other nuclei in the brain, e.g. the superior colliculus (Perry and Cowey, 1984; Kisvárdy et al., 1991) and pulvinar (Cowey et al., 1994), or with neurones in the dLGN which project directly to extrastriate cortex (Benevento and Yoshida, 1981; Fries, 1981; Yukie and Iwai, 1981; Bullier and Kennedy, 1983).
Removal of an entire cortical hemisphere (hemispherectomy) causes extensive subcortical degeneration (Peacock and Combs, 1965; Ueki 1966; Boire et al., 2000), and one might therefore expect retinal degeneration to be even more severe than after lesions restricted to striate cortex. This raises the possibility that the inability of hemispherectomized patients to respond explicitly to visual stimuli is simply due to the amount of degeneration of early visual pathways rather than the absence of extrastriate cortex. We tested this by using pattern electroretinography.
Electroretinography involves recording electrical potentials in the microvolt range from the retina in response to light or patterned visual stimuli (for reviews, see Regan, 1989; Berninger and Arden, 1991). Steady-state responses, elicited by temporal contrast-modulation of patterned stimuli such as gratings, consist of a component at the fundamental frequency (f0) of modulation, and a component at twice the fundamental frequency (2f0, or the second harmonic). These may correspond to distinct linear (light-dependent) and non-linear (spatial frequency-dependent) processes, respectively (Baker and Hess, 1984; Hess and Baker, 1984; Thomson and Drasdo, 1987), although some of the latest evidence suggests that the non-linear component may be both light- and spatial frequency-dependent (see Spekreijse et al., 1973; Riemslag et al., 1985; Viswanathan et al., 2000). The pattern-evoked 2f0 responses reflect the activity of retinal ganglion cells in that they have bandpass spatial tuning (Arden and Vaegan, 1983; Korth, 1983; Hess and Baker, 1984) and are abolished by retrograde degeneration of the entire ganglion cell population after optic nerve section in cats, monkeys and people (Maffei and Fiorentini, 1981, 1982; Dawson et al., 1982; Maffei et al., 1985; Baker et al., 1988; Morrone et al., 1994b). In addition, it has been shown that isoluminant colour gratings can be used selectively to elicit pattern-specific responses from the wavelength-sensitive Pß ganglion cells in the normal retina (Morrone et al., 1994a, b).
We therefore used pattern electroretinography to assess retinal function in patients with complete cerebral hemispherectomy. Our results show that ganglion cell activity is not abolished following hemidecortication in human patients, which not only is consistent with a recent anatomical study of the retinae of hemispherectomized monkeys demonstrating that hemispherectomy in monkeys does not produce more transneuronal retinal degeneration than occipital damage (Herbin et al., 1999), but shows in addition that the surviving ganglion cells are capable of processing visual information. This supports the proposal that intact extrastriate cortex is necessary for mediating voluntary responses to visual stimuli in the scotoma (King et al., 1996a).
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Methods |
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Steady-state pattern electroretinograms (PERGs) elicited by sinusoidal gratings whose contrast was temporally modulated were recorded from the eyes of three patients with cerebral hemispherectomy, and of one patient with almost total unilateral striate cortex damage. The subjects' informed consent to take part in the experiments was obtained in accordance with the declaration of Helsinki, and ethical approval obtained from the Central Oxford Research Ethics Committee (COREC:93.121).
Subjects
The three hemispherectomized patients, M.M., D.K. and S.D., had previously undergone complete cerebral hemispherectomy for the relief of uncontrollable epileptic seizures. The procedure (Adams, 1983) involved the removal of the entire cortex on one side of the brain, sparing the basal ganglia. Structural MRIs of the brain of one of the patients are shown in Fig. 1.
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The patients' clinical details are summarized in Table 1
. The time of onset of neurological symptoms ranged from birth to 3 years, and the age at surgery ranged from 11 to 27 years. In each case, surgery caused a homonymous hemianopia in the contralateral visual field, with no detectable explicit or implicit residual vision in the blind field (King et al., 1996a). Other aspects of pre- and postoperative motor, cognitive and behavioural function of two of the subjects (S.D. and D.K.) have been described elsewhere (Beardsworth and Adams, 1988).
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The fourth subject, G.Y., had a unilateral lesion in his left occipital lobe caused by a traffic accident at the age of 8 years. The damage affected most of the occipital cortex while sparing only the occipital pole, causing a right homonymous hemianopia with macular sparing extending to 3.5° in the blind hemifield. G.Y.'s residual visual capacities have been extensively documented, and include the ability to detect, localize and discriminate transient stimuli presented in his field defect (Barbur et al., 1980
; Blythe et al., 1986, 1987; Weiskrantz et al., 1991, 1995; Barbur et al., 1994; King et al., 1996a; Azzopardi and Cowey, 2001). His sensitivity is not necessarily mediated by extra-ocularly scattered light (King et al., 1996a; Azzopardi and Cowey, 1997, 2001), or by spared islands of cortex in his field defect (Kentridge et al., 1997).
Stimuli
The visual stimuli were vertical sinusoidal luminance gratings (mean luminance 102 cd/m2) of 2.0 and 12.0 cycles per degree (c.p.d.), designated as A2 and A12, and photometrically isoluminant chromatic (red–green) gratings (mean luminance 20.25 cd/m2) of 2.0 c.p.d. (designated as C2), whose contrast was modulated between 0 and 95% sinusoidally at a temporal frequency of 7.95 Hz. In normal subjects, the PERG elicited by contrast-modulated gratings is bandpass with respect to both spatial and temporal frequency, with optimal parameters at the fovea of 4 c.p.d. modulated at 8 Hz. It is influenced by several other factors including the size of the stimulus, its contrast, its mean luminance and its retinal eccentricity (Hess and Baker, 1984). The parameters of A2 and C2 were selected for being optimal after preliminary experiments with two normal control subjects (authors P.A. and S.M.K.) using eccentric stimuli centred on the horizontal meridian. A12 was selected as a control condition because the signal to noise ratio at a spatial frequency of 12 c.p.d. (the high frequency response cut-off) is negligible, thus providing an estimate of noise under realistic experimental conditions. In the normal retina, therefore, we would predict the rank order of 2f0 response amplitudes to be A2 > C2 > A12, as confirmed by results obtained from the two control subjects shown in Fig. 2.
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The stimuli were generated using custom software running on a microcomputer with a 33 MHz 80486DX processor (Intel) and an SVGA video card (STB Systems) with 8-bit grey level resolution, and displayed with gamma correction on a 15-inch VDU (Chuntex Electronics, Taipei, Taiwan; Model 1565, 0.27 mm pitch, 1024 x 760 pixels in a viewing area of 255 x 205 mm, calibrated with a Minolta LC1500 photometer), at a non-interlaced frame rate of 80 Hz.
The gratings were viewed monocularly (to enable each half retina of each eye to be assessed in isolation) in 12x10 degree fields at 6–18 degrees of eccentricity centred on the horizontal meridian at a distance of 1.14 m, while the subject rested the head in a chin rest and gazed at a stable fixation point in ambient light that just allowed reading. Fixation was monitored by means of infra-red-sensitive video camera and monitor. Trials were initiated from the keyboard of the stimulus-generating microcomputer by an investigator who watched the subject's eye on the closed-circuit TV monitor. The gratings were presented to each hemifield of each eye in 10 blocks of 128 contrast reversals each. The order of presentation differed from subject to subject.
Recording
Differential ERG signals were recorded using gold-coated Mylar electrodes placed in the lower fornix of the eye, with a standard Ag/AgCl reference electrode on the skin of the adjacent temple and an earth lead attached to the earlobe. Signals were amplified with an optically isolated pre-amplifier (NL85A, NeuroLog System, Digitimer Ltd, Welwyn Garden City, UK), further amplified (NL104 preamplifier) up to a total amplification of x20 000 and bandpass filtered between 1 and 100 Hz (NL125 filter), before being sampled with 12-bit resolution at a rate of 64 samples per reversal, and stored on a second microcomputer with a 33 MHz 80486DX processor (Intel) using a CED 1401 Plus interface and Spike 2 (Version 4) software (Cambridge Electronic Design Ltd, Cambridge, UK). A pulse emitted by the stimulus generator at the start of each contrast reversal was used to ensure that the signals could be synchronized with the stimulation. The signals recorded during each block of reversals were averaged off-line, a process that incorporated threshold rejection of reversals contaminated by blink and eye movement artefacts. The averaged signals were then weighted with a raised cosine function, and a fast-fourier transform applied (see Bach and Meigen, 1999) to determine the amplitude and phase of the second harmonic (2f0 or twice the fundamental frequency) corresponding to the pattern-specific component.
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Results |
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PERGs with visibly recognizable 2f0 components in the averaged signals were obtained from each hemiretina of each patient with each stimulus (Figs 3–6
). The quality of the data depended on the patients' ability to hold fixation without blinking, which varied among patients. Within-subject differences between the mean amplitudes of the 2f0 components of the signal were analysed using three-way analysis of variance (ANOVA) (Generalised Linear Models, SPSS v.9.0, SPSS, Chicago, Ill., USA) with eye (left or right), hemifield (sighted or blind) and stimulus (gratings A2, C2 and A12) as factors. The results are presented in Table 2.
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Patient S.D. (right hemispherectomy)
Patient S.D. could fixate steadily without blinking for long periods of time, and therefore PERGs with a clear 2f0 component were easily obtained (Fig. 3A
). There were consistent and systematic differences in the amplitudes of the 2f0 component of the averaged signals across the main conditions of the experiment (Fig. 3B). First, the 2f0 amplitude was always largest in response to stimulus C2 (isoluminant chromatic grating, 2 c.p.d.), and always smallest in response to stimulus A12 (achromatic grating of 12 c.p.d.), irrespective of eye or visual hemifield. Secondly, there was an interaction between visual hemifield and eye, such that the amplitude of the 2f0 component elicited in the nasal retina was greater than that elicited in the temporal hemiretina of the same eye, irrespective of stimulus and irrespective of whether the hemifield was sighted or blind. A three-way ANOVA with eye, hemifield and stimulus as factors revealed that the differences in amplitude across stimuli [F(2,107) = 3.161, P = 0.046] and the eye x hemifield interaction [F(1,107) = 6.671, P = 0.11] were statistically significant. There were no significant differences between the mean amplitudes of the 2f0 component of the different hemifields [sighted or blind; F(1,107) = 0.027, n.s.] and there was no significant stimulus x hemifield interaction [F(2,107) = 0.07, n.s.].
Patient D.K. (right hemispherectomy)
Patient D.K. had trouble in maintaining fixation and suppressing blinks, and the signals were therefore noisier than those of S.D. However, he was willing to repeat blocks of trials if necessary and it was therefore possible to obtain PERGs with recognizable 2f0 components in the averaged signal (Fig. 4). A three-way ANOVA with eye, hemifield and stimulus as factors revealed that the differences in 2f0 amplitude across stimuli [F(2,103) = 4.68, P = 0.012] and across eyes [F(1,103) = 4.861, P = 0.03] were statistically significant, but in this subject there was no significant eye x hemifield interaction [F(1,107) = 0.123, n.s.]. As before, the 2f0 amplitude of the signals elicited by isoluminant chromatic gratings was larger than those elicited by achromatic gratings. There were no significant differences between the mean amplitudes of the 2f0 component of the different hemifields [sighted or blind; F(1,107) = 0.291, n.s.] and there was no significant stimulus x hemifield interaction [F(2,107) = 0.769, n.s.].
Patient M.M. (left hemispherectomy)
Patient M.M. found it difficult to maintain fixation without blinking or shutting her eyes, and often rubbed her eyes or touched the electrode leads. Many of the recordings were rather noisy as a result. She also found the flickering stimuli aversive after a while, and the experiment was terminated at her request before the conditions worst-affected by artefacts could be repeated. However, it was possible to obtain averaged PERGs with recognizable 2f0 components from the blind hemiretinae (Fig. 5A). A three-way ANOVA with eye, hemifield and stimulus as factors revealed significant differences in the amplitude of the 2f0 component across stimuli [F(2,101) = 10.762, P < 0.001] and across hemifields [F(1,101) = 17.251, P < 0.001], and a significant eye x field x stimulus interaction [F(2,101) = 11.677, P < 0.001]. These effects are dominated by the extraordinarily weak responses elicited in the left (sighted) field of the right eye by stimuli C2 and A12, which we attribute to the artefacts described above.
Patient G.Y. (left striate cortex lesion)
Subject G.Y. was excellent at fixating without blinking, and PERGs with reasonably good 2f0 components were obtained, though the averaged responses were relatively weak (Fig. 6). A three-way ANOVA with eye, hemifield and stimulus as factors revealed a significant difference in the amplitude of the 2f0 component across stimuli [F(2,108) = 3.936, P < 0.05] and a significant eye x field interaction [F(1,108) = 6.888, P < 0.05], but there were no significant differences between the mean amplitudes across hemifields [F(1,108) = 0.908, n.s.] or hemifield x stimulus interaction [F(2,108) = 0.035, n.s.].
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Discussion |
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The purpose of this experiment was to establish whether it is possible to record pattern-specific retinal signals, diagnostic of retinal ganglion cell function, from patients with long-standing cerebral hemispherectomy. As summarized in Table 2
, the three hemispherectomized patients showed significant effects of stimulus on the amplitude of the pattern-specific 2f0 component of the PERG, irrespective of whether the blind or the sighted hemiretina was stimulated. This indicates that there must be a functional population of ganglion cells in their retinae. For the two patients whose data were relatively free of artefact, the amplitude of the response elicited by isoluminant chromatic gratings was greater than the response elicited by achromatic gratings. This was unexpected, given that the retinal degeneration caused by striate cortical lesions affects only the wavelength-sensitive Pß ganglion cells and not the broad-band P ganglion cells (Cowey et al., 1989). Most importantly, the 2f0 amplitudes did not differ significantly between hemifields, implying that the signals were largely unaffected by retinal ganglion cell degeneration in the blind hemiretina. The fact that signals were elicited from the blind hemiretinae indicates that some retinal ganglion cells had survived hemispherectomy and could respond to visual stimuli. Similar results were obtained from the patient with a unilateral striate cortical lesion.
Comparison with previous studies
Pattern-specific electroretinograms from the impaired retina of patients blinded by occipital cortical damage have been recorded previously by Skrandies and Leipert (1988), Stoerig and Zrenner (1989) and Porello and Falsini (1999). Skrandies and Leipert found no significant differences between the transient PERGs recorded from the impaired and normal hemiretinae. Our results are consistent with this in that there were no significant differences between hemifields in the amplitude of the 2f0 signal in the cortically blind subject, G.Y., as well as in two of the hemispherectomized patients. The exceptional results, obtained from patient M.M., were most likely due to the unusually weak recordings obtained with stimuli C2 and A12 from the left field in her right eye (Fig. 5). In contrast, Stoerig and Zrenner (1989) reported effects on the steady-state PERG consistent with the loss of ganglion cells in the affected part of the retina, namely a one- to twofold reduction in the peak amplitude of the signal depending on temporal frequency, increased variability of the measured phase of the response, a two- to fourfold reduction in the optimal spatial frequency, and a twofold reduction in the optimal temporal frequency. Porello and Falsini (1999) recorded PERGs from eight cortically blind patients and found that signals elicited by gratings with a spatial frequency of 5 c.p.d. modulated at 6 Hz (intended to stimulate predominantly P ganglion cells) were significantly attenuated, whereas signals elicited by gratings of 0.58 c.p.d. modulated at 15 Hz (intended to stimulate predominantly Pß ganglion cells) were not attenuated. This is consistent with the fact that striate cortical ablations cause selective transneuronal degeneration of Pß ganglion cells (Cowey et al., 1989). The reason we failed to find any significant effect of hemifield in this study could be that, at 8 Hz, our stimuli were better suited to stimulating both P and Pß ganglion cells than just the Pßs, especially as there is considerable overlap in the spatiotemporal sensitivity of the parvocellular and magnocellular systems (Schiller et al., 1990). This is supported by the fact that Stoerig and Zrenner (1989) also found no difference between hemifields in their subject F.S. at this particular temporal frequency, despite finding a significant difference at lower frequency.
Porello and Falsini (1999) also found consistent differences in the amplitude of the 2f0 signal between nasal and temporal hemiretinae in normal subjects, consistent with nasotemporal anisotropy in ganglion cell distribution (Perry and Cowey, 1985; Curcio and Allen, 1990; Azzopardi and Cowey, 1996). These differences were accentuated in cortically blind patients when measured with the 6 Hz stimuli (but not the 15 Hz stimuli), again reflecting selective loss of Pß ganglion cells in the impaired hemiretinae. Although we found no significant effect of hemifield (with the exception of M.M., discussed above), there was a significant eye x hemifield interaction in hemispherectomized patient S.D., and the striate-lesioned control G.Y. In S.D.'s case, the pattern of results conforms to the prediction that responses recorded from the impaired nasal hemiretina should be consistently greater than those recorded from the impaired temporal retina, and responses from the sighted nasal hemiretina greater than those from the sighted temporal retina (Fig. 3). In G.Y.'s case, however, the pattern was reversed, with responses in the temporal hemiretina tending to be greater than those in the corresponding nasal hemiretina (Fig. 6).
Responses to achromatic stimuli
Several factors can affect the amplitude of the signal in steady-state PERGs, including the spatial frequency, temporal frequency, mean luminance, contrast, size, eccentricity and chromaticity of the stimulus, stability of fixation and state of accommodation, and the extent of retinal ganglion cell degeneration (Maffei and Fiorentini, 1981; Hess and Baker, 1984; Morrone et al., 1994a, b). The properties of stimulus A2 used in the present study (spatial frequency of 2 c.p.d., temporal frequency of 8 Hz, mean luminance of 102 cd/m2 contrast of 90%, and area of 12° x 10°) were near-optimal for control subjects at the eccentricity used with our apparatus. Stimulus A12 (12 c.p.d.) differed from A2 only in its spatial frequency, selected because it corresponds to the high spatial frequency cut-off for the 2f0 signal for a central stimulus. In normal subjects, there was a conspicuous difference between the responses elicited by these two spatial frequencies (Fig. 2). Furthermore, whereas the response to stimulus A2 attenuated dramatically in the peripheral visual field, in accordance with previous studies (Hess and Baker, 1984) and reflecting the fact that ganglion cell density is highest at the fovea and decreases rapidly towards the periphery (Perry and Cowey, 1985; Curcio and Allen, 1990; Azzopardi and Cowey, 1996), the response to stimulus A12 did not attenuate significantly, suggesting that the signal elicited by this stimulus was not different from noise levels.
ANOVA revealed significant effects of stimulus in all four patients (Table 2). In one of the hemispherectomized patients (S.D.) the responses elicited by A2 were consistently greater than those elicited by A12 as predicted, irrespective of whether the sighted or impaired hemiretina was stimulated. This was also the case for another hemispherectomized patient, D.K., in his right eye, but not in his left eye where the responses to the two stimuli were about the same. In the two remaining patients, M.M. (hemispherectomized) and G.Y. (striate cortical lesion), the pattern was less consistent. In some cases the responses to the two stimuli were indistinguishable. This could mean that there were no functional ganglion cells in these hemiretina. However, absence of a signal is a much less reliable indicator of total retinal dysfunction than a clear signal is of retinal function, because it can be abolished though poor accommodation alone (Hess and Baker, 1984). This is underlined by the fact that at least one hemifield in each patient in which there was no discernable difference in the response to the two stimuli was a sighted hemifield (e.g. M.M., left eye, left hemifield; G.Y., right eye, left field).
Occasionally (patient M.M., right eye, blind hemifield; and G.Y., left eye, sighted hemifield), the responses to A12 exceeded the response to A2. This was unexpected in that no signal would be expected to be weaker than noise! In M.M.'s case, the explanation is probably straightforward, namely she rubbed her eye during the run of data collection, and it was not possible to repeat the run due to fatigue. Removal of the affected data from the analysis reduced the mean signal to a level indistinguishable from A2. The explanation in G.Y.'s case is less obvious. One possibility is that non-linearity in the screen output could have contaminated the high frequency stimulus with a low frequency artefact, to which the retina could respond. However, this probably does not explain why among four subjects the effect was only observed in G.Y.'s left eye.
Responses to isoluminant chromatic stimuli
Morrone et al. (1994a, b) previously demonstrated that high-contrast, red–green gratings elicited strong 2f0 signals at isoluminance in both people and monkeys, which they argued was indicative of activity of wavelength-sensitive Pß ganglion cells. We therefore used photometrically isoluminant red–green gratings (2 c.p.d., contrast 95%, mean luminance of 20.25 cd/m2) as one of our stimuli (C2), in the expectation that the 2f0 components elicited would be relatively weak (as illustrated in Fig. 2) or non-existent, depending on the amount of Pß ganglion cell degeneration incurred. However, we found unexpectedly that in the two hemispherectomized patients from whom it was possible to obtain relatively noise-free data, the responses to C2 were larger than the responses to A2 (Figs 3 and 4). There are several possible explanations. The first is that the colours in the stimulus, though photometrically isoluminant, were not isoluminant with respect to the patients' receptors, as would be the case if retinal degeneration caused a change in the ratio of long to medium wavelength-sensitive cones projecting to the surviving ganglion cells. This is difficult to address with hemispherectomized patients as it is impossible to determine the subjective isoluminant point psychophysically with subjects who cannot respond explicitly to stimuli presented in their field defects. But departures from isoluminance cannot be the only explanation, because even with a totally red-blind or green-blind individual the maximum possible achromatic contrast would be 90%, i.e. no higher than the contrast of the achromatic stimulus A2, which therefore would not explain why the response to C2 tended to be stronger than the response to A2. A second possibility is that hemispherectomy causes more extensive degeneration of P ganglion cells than of Pßs, but this seems highly unlikely as it is the Pßs and not the Ps which degenerate following lesions restricted to the striate cortex (Cowey et al., 1989). The third explanation is that responses to isoluminant chromatic gratings did not reflect the activity of chromatic processes. McKeefry et al. (1997) have suggested that the PERG response to chromatic stimuli at high contrasts could be dominated by Pß cell responses, but that at lower contrast it was more likely to be due to the activity of P ganglion cells. The latter responses could be mediated by latency differences between the L and M cone inputs to the ganglion cells (Lee et al., 1989; Smith et al., 1992; Lee et al., 1993; Stromeyer et al., 1997). This is relevant because, although high contrast gratings were used in these experiments, significant degeneration of the Pß ganglion cells would mean that the stimuli were effectively weak to the parvocellular system, so unmasking the responses of the P cells.
Implications for blindsight
Early studies of patients with cerebral hemispherectomy reported sparing of several visual capacities in the scotoma, including target detection, target localization by pointing and eye movements, form discrimination, motion detection and velocity discrimination (Perenin, 1978, 1991; Perenin and Jeannerod, 1978; Ptito et al., 1987, 1991; Braddick et al., 1992). These capacities are also present in blindsighted patients with lesions restricted to the striate cortex or optic radiations, and so it was concluded that blindsight must be mediated by the superior colliculus—either the ipsilesional colliculus alone, or through an influence on the contralesional colliculus via the inter-tectal commissure (for reviews, see Weiskrantz, 1986; Stoerig and Cowey, 1997). However, since the earliest studies of hemispherectomized patients were criticized for having poor controls for potential artefacts (Campion et al., 1983), and despite evidence for implicit processing in the scotoma as revealed by spatial summation across the vertical meridian (Tomaiuolo et al., 1997), independent studies have found that hemispherectomized patients cannot explicitly respond to, or discriminate, visual stimuli other than those associated with artefacts, e.g. scattered light and response bias (Campion et al., 1983; King et al., 1996a, b; Barton and Sharpe, 1997; Faubert et al., 1999). In other words, the subcortical pathways that survive hemispherectomy—including the superior colliculus—are unable to mediate explicit responses to visual stimuli in the scotoma in the absence of overlying cortex. As long as the remaining visual system does not degenerate completely after hemispherectomy, this implies that where striate cortex is damaged or absent, ipsilateral extrastriate cortex is necessary for mediating residual vision (King et al., 1996a).
The retina is a useful indicator of early visual system degeneration, as the death of neurones in retinofugal targets and the resulting loss of functional synaptic connexions with retinal projections normally leads to the death and degeneration of ganglion cells in the retina itself. Thus, after ablations of striate cortex, up to 85% of Pß ganglion cells are lost as a result of the degeneration of projection neurones in the lateral geniculate nucleus, which would normally project directly to the cortex, and the survival of the remaining Pß ganglion cells, as well as the Ps, is attributable to the existence of functional connexions with other parts of the brain such as the superior superior colliculus (Perry and Cowey, 1984; Kisvárdy et al., 1991) and pulvinar nucleus (Cowey et al., 1994), or with neurones in the dLGN which project directly to extrastriate cortex (Benevento and Yoshida, 1981; Fries, 1981; Yukie and Iwai, 1981; Bullier and Kennedy, 1983). Since our preliminary report (Azzopardi et al., 1996), an anatomical investigation of the effects of cerebral hemispherectomy in monkeys found that the amount and distribution of retinal degeneration after hemispherectomy is similar to that found after striate cortex lesions, i.e. up to 70% of ganglion cells degenerate following hemispherectomy, almost certainly involving Pß ganglion cells exclusively (Herbin et al., 1999). The precise amount of degeneration depends on the age that the lesion was incurred, as it does with striate cortex lesions (Dineen and Hendrickson, 1981; Weller and Kaas, 1989), with `early' lesions sustained in infancy (4–6 months of age) being the most effective. On this basis, we might not expect to find complete degeneration of ganglion cells in hemispherectomized patients. This is confirmed by the results of the present study, in which PERGs recorded from the blind hemiretinae of hemispherectomized patients show that a substantial number of ganglion cells must have survived the procedure and retained their visual responsiveness. If the monkey is a representative model then the amount of degeneration in the retinae of the patients tested in this particular study could be relatively small, as the surgery was carried out beyond infancy (range 11–27 years of age).
The existence of ganglion cells in the retina tens of years after surgery suggests strongly that some targets of direct retinal projections have not degenerated completely as a result of complete removal of a cortical hemisphere, and that they are capable of mediating responses to visual stimulation. In monkeys, although there is some degeneration in the superior colliculus following hemispherectomy, it is incomplete (~ 30% loss of neurones and volume; Théoret et al., 2001). It is not known how the loss is distributed between visual and non-visual neurones, but the persistence of retino-collicular projections as demonstrated using amino acid labelling (Boire et al., 2000; Théoret et al., 2001), and also the presence of ganglion cells in the retina (Herbin et al., 1999), suggests that not all visual neurones in the superior colliculus degenerate. But this still leaves open the question of whether or not the surviving projections are functional. This is especially important because functional MRI studies have so far been unable to demonstrate activation of subcortical structures, including the superior colliculus by visual stimulation in blind fields of hemispherectomized patients (Bittar et al., 1999), despite the fact that it has been shown in a patient with a striate cortex lesion (Sahraie et al., 1997).
Overall, the electrophysiological and anatomical evidence suggests that the retino-collicular pathway does not degenerate completely as a result of cortical hemispherectomy, and is capable of processing visual inputs (Azzopardi et al., 1996; Herbin et al., 1999; Boire et al., 2000; Théoret et al., 2001; the present study). Given that it is possible to elicit implicit behavioural responses to visual stimuli in the blind field (Tomaiuolo et al. 1997), but not explicit ones such as pointing and verbal reports (King et al., 1996a, b), these findings are consistent with the proposal that intact extrastriate cortex is necessary for mediating voluntary responses to visual stimuli in the scotoma (King et al., 1996a).
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We wish to thank our subjects for their cooperation. This work was supported by grants from the MRC and the Royal Society.
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Received November 6, 2000. Revised February 1, 2001. Accepted February 22, 2001.
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